Investigation on the Stereoselective Construction of Fused-Ring Frameworks by Using Photochemical Properties of N-Heteroaromatic Compounds

<p>Indoline-fused cyclic compounds constitute an important class of bioactive natural products, and they are also typical structural motifs in useful organic compounds exemplified by pharmaceuticals. Novel fused cyclic indoline frameworks attract a great deal of interest in bioactive screening for new pharmaceutical candidates. In conjunction with a recent trend in drug discovery, i.e., “escape from flatland” concept, conformationally constrained small-ring-fused compounds, such as cyclobutanes, have interested researchers in drug discovery due to the growing demand for less lipophilic conformationally restricted analogues of known scaffolds rather than the rigid aromatic compounds. To date, a number of synthetic methods have been reported for indoline derivatives fused with 5- or 6-membered ring, whereas those that contain a cyclobutane ring are much less explored. The photochemical [2+2] cycloaddition reaction is one of the most popular and facile methods of constructing 4-membered cyclic compounds. Though the reaction between 1-acylindoles and substituted ethenes is known for decades, several issues remains to be improved, including regio- or stereoselectivity and functional group transformability. We have developed photochemical [2+2] cycloaddition reactions of 1- or 3-(ω-allenyl) indole derivatives that give a variety of methylenecyclobutane-fused indoline frameworks. We newly found that 3’,4’-dimethylacetophenone (diMeOAP) acts as a quite effective photosensitizer in this kind of reaction. The 3’,4’-diMeOAP-sensitized photoreaction was successfully extended to preparation of cycloheptane-fused indolines and [2+2] cycloaddition of 7-azaindoles. The methylenecycloprapane derivatives turned out to be useful precursors for various ring-fused N-heterocyclic compounds via an epoxidation/skeletal rearrangement sequence.</p>